Inherited retinal dystrophies (IRDs) are a large group of diseases that are genetically and clinically heterogeneous. They are characterized by progressive vision loss, although the age at which legal blindness is reached is variable. Although individually rare, collectively IRDs affect approximately 1 in 2000 individuals worldwide (Berger et al, 2010). The most prevalent form of IRD is the group of pigmentary retinopathies, which are characterised by degeneration of the photoreceptor cells of the retina and the presence of pigment deposits visible on the fundus. A good example is choroideremia (CMH). CHM is an X-linked pigmentary retinopathy that represents 2% of IRDs (Bocquet et al, 2013). It is characterized by night blindness in childhood followed by progressive loss of the visual field resulting in blindness by 40 to 50 years of age. CHM has a characteristic phenotype, comprising pigment deposits and an atrophy of the choriocapillaris of the choroid, situated just behind the retina. There is a single causative gene, CHM, which encodes REP1, Rab escort protein-1 (Seabra et al, 1992) a ubiquitous chaperon protein allowing the correct prenylation of Rab GTPases and subsequent delivery to their membrane targets.
The retina in general is highly amenable to gene therapy because i) it is accessible via non-invasive routes, ii) it is small and enclosed allowing the use of low vector doses, and iii) the presence of a blood-retina barrier, composed of the tight junctions of the retinal pigment epithelium (RPE) and the non-fenestrated capillaries of the retinal circulation, prevents leakage into the circulation and renders it immuno-privileged (Colella et al, 2009). These positive attributes led to the first clinical trials for retinal gene therapy in 2008 (Bainbridge et al, 2008; Maguire et al, 2008) that were rapidly followed by others (Bennett et al, 2012; Hauswirth et al, 2008; Jacobson et al, 2012; Maguire et al, 2009). The target IRD, Leber congenital amaurosis (LCA), arises due to mutations in the RPE-specific gene, RPE65 (Marlhens et al, 1997), which encodes a key enzyme of the visual cycle. RPE65 was successfully vehicled into the RPE using a recombinant adeno-associated virus serotype 2 vector (AAV2/2). The positive results provided the proof-in-principle that gene transfer can ameliorate sight in visually impaired subjects and prompt the researchers to the identification of the most efficient vectors, especially for expression a polynucleotide of interest in RPE.